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PHYSICIAN PERSPECTIVE Viewpoint based on the following article: J Am Soc Nephrol 2009;20(4):893-900.

April 2009

Reported by:

Ellen D. Burgess, MD, FRCPC, FACP

Director, Hypertension Research Clinic, Foothills Medical Centre, Calgary, Alberta

Professor of Medicine, University of Calgary, Calgary, Alberta

Although renin-angiotensin system (RAS) inhibitors can redress albuminuria, they do not necessarily reduce albuminuria in concordance with blood pressure (BP). Thus to achieve optimal renoprotection, far higher doses than the maximally approved antihypertensive doses may be needed.

As demonstrated by Eijkelkamp et al. (J Am Soc Nephrol 2007;18:1540-6) in a post-hoc analysis of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan), more patients experiencing both reductions in systolic BP (SBP) and reductions in albuminuria were seen in those randomized to ARB therapy.

Regarding renal outcomes, results confirmed that patients who achieved lesser reductions in SBP were at increased risk for end-stage renal disease (ESRD) compared to those who had a <u>></u>15 mm Hg reduction in SBP. Conversely, patients with robust decreases in both SBP and albuminuria had the most favourable clinical outcomes. The risk of progressing to ESRD was also lowest among those with lowest levels of residual albuminuria across all levels of SBP.

These findings bring into question the need to monitor not just BP response to therapy but anti-albuminuric responses as well. Yu et al. indicated that maximal antifibrotic effects in the kidney are only possible when ultra-high doses of an ARB are used (J Am Soc Nephrol 2007;18:750-9). The reason may be that there are many more angiotensin type 1 receptors in the kidney and blocking all of them takes a greater dose of an ARB than the dose needed for BP reduction.

To that end, SMART (Supra Maximal Atacand Renal Trial) was designed to assess the potential benefits and risks of using dosages of the ARB candesartan up to 128 mg/day compared with the highest approved antihypertensive dose (at the time the study was started) of 16 mg/day in patients with persistent proteinuria <u>></u>1 g/day despite receiving the maximally approved dosage for seven weeks prior to enrolment.

SMART

Out of 346 patients enrolled, 269 continued to have persistent proteinuria <u>></u>1 g/day despite a maximally approved dose of candesartan 16 mg daily. Patients either continued on 16 mg/day or were titrated up to 64 mg/day or 128 mg/day for 30 weeks (Figure 1). Upon enrolment, median levels of serum creatinine was 130.0 mmol/L and serum potassium was 4.5 mmol/L.

Figure 1.

At study end point, the geometric mean of the 24-hour urine protein excretion had dropped from 2.85 g/day at randomization to 1.79 g/day for patients receiving the highest dose, representing in the intent-to-treat population a mean percentage reduction of 33.05% compared to the 16-mg group (P<0.0001) (Figure 2). In the per-protocol population, the mean reduction in proteinuria was 44.34% for the 128-mg group (P<0.0001). In a subanalysis, similar proteinuria reduction was observed irrespective of whether patients had diabetes or non-diabetic kidney disease.

The additional antiproteinuric effect of the supramaximal dose was independent of BP reduction. No difference in BP reduction was observed between the three groups either at randomization or at study end point. There was also no correlation between BP reduction and reduction in proteinuria. The mean reduction in proteinuria in the 64-mg group was 16.91% compared with the 16-mg group who obtained a mean change in proteinuria of -7.49% from study enrolment to end point.

However, response to treatment appeared to be influenced by the level of proteinuria at randomization. The 128-mg dose reduced proteinuria by 43.62% in patients with a level of <u><</u>3 g/day and by 25.29% in those with levels of >3 g/day.

From randomization to study end point, there was no difference in the change in serum creatinine levels or eGFR between the three groups. Eleven patients discontinued treatment due to increases in serum potassium >5.5 mmol/L; however, no significant differences in serum potassium were seen among
roups.

Figure 2.

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Results from ROAD

If SMART indicated that supramaximal doses of candesartan could induce significantly greater reductions in proteinuria than antihypertensive doses, it is not the only study to suggest that greater inhibition of the RAS confers greater renoprotection in patients with proteinuria and renal insufficiency although not, in this particular instance, diabetes. In the Renoprotection of Optimal Antiproteinuric Doses (ROAD) study, Hou et al. (J Am Soc Nephrol 2007;18:1889-98) evaluated whether higher doses of either benazepril or losartan could safely improve renal outcomes in patients at risk for ESRD. A total of 360 patients were initially enrolled, although 50 withdrew during the pretitration phase mainly because of dry cough.

Patients received either conventional-dose benazepril (10 mg/day), a median uptitrated dose of 20 mg/day (range 10 to 40 mg), a conventional dose of losartan (50 mg/day) or an uptitrated dose (median 100 mg/day, range 50 to 200 mg).

At a median follow-up of 3.7 years, 15 out of 84 patients (17.9%) on titrated antiproteinuric doses of benazepril experienced the primary end point of a doubling of the serum creatinine, ESRD or death compared with 26 out of 83 patients (31.3%) in the conventional dose group (P=0.025). Similarly, of the losartan cohorts, 13 out of 84 patients (15.5%) on higher antiproteinuric doses reached the primary end point compared with 26 out of 88 patients (29.5%) of those on standard dose.

The secondary end point was change in the level of proteinuria and rate of progression of renal disease. Titrated antiproteinuric doses of both drugs led to significantly greater reductions in proteinuria from baseline with a median reduction of 50% at month 36 in the benazepril arm and 53% in the losartan arm. Comparable reductions were observed in the conventional treatment arms: 38% for benazepril and 41% for losartan.

Hyperkalemia did occur in 4.4% of patients who received benazepril and an identical percentage of patients who received losartan but there were no dosage-related differences between the treatment groups with respect to adverse events.

Thus, titrated antiproteinuric doses of both the ACE inhibitor and the ARB reduced the likelihood that patients would reach the primary end point by 51% compared with antihypertensive doses and this decrease remained significant after adjustment for SBP. Both SMART and ROAD support the use of increased doses of RAS inhibitors to maximize reductions in proteinuria and improve renal outcomes in patients at risk for ESRD. Provided the dose is judiciously titrated up and serum potassium is carefully monitored, optimal renoprotection may be achieved with the use of supramaximal doses of RAS inhibitors regardless of their effect on BP.

Proteinuria and Cardiovascular Disease

If proteinuria is widely recognized as a marker for renal damage, it is also appreciated as a risk factor in CV disease (CVD). Using the cohort from the Framingham Heart Study, Culleton et al. (Am J Med 2000;109:1-8) found that over 17 years of follow-up, baseline proteinuria was associated with all-cause mortality in men at a hazard ratio (HR) of 1.3 for both trace and greater-than-trace proteinuria. In women, trace proteinuria was associated with a slightly greater risk of CVD death at a HR of 1.6 as well as all-cause mortality at a HR of 1.4.

Findings from a meta-analysis of some 26 cohort studies involving 169,949 participants indicated that the presence of proteinuria was associated with an approximately 50% increase in coronary risk after adjustment for known risk factors (Perkovic et al. PLoS Med 2008;5(10):e207). For albuminuria, there was also evidence of a dose-response relationship in the same meta-analysis: those who had evidence of microalbuminuria were at 50% greater risk of coronary artery disease (CAD) than those without and those with macroalbuminuria had more than double the risk. These data support the association between proteinuria and CAD in the general population. Microalbuminuria—now accepted as a risk factor for CVD—is similarly implicated in CV mortality although not to as great an extent as gross proteinuria, at least in individuals with type 2 diabetes.

In a population-based study of 840 patients with older-onset diabetes, Valmadrid et al. (Arch Intern Med 2000;160:1093-100) found patients with microalbuminuria and gross proteinuria at baseline had significantly higher CV mortality rates after 12 years of follow-up compared with patients with normoalbuminuria (all other risk factors controlled for). Their analysis also showed that both microalbuminuria and gross proteinuria were significantly associated with mortality from all causes as well as from CVD, cerebrovascular disease and CAD.

Perhaps most intriguing is evidence from de Zeeuw et al. (Circulation 2004;110:921-7), who identified albuminuria as a therapeutic target for CV protection in patients with type 2 diabetic nephropathy. Using data from RENAAL, investigators sought to determine whether reducing albuminuria in this patient population would lower the CV event rate, and if the degree to which albuminuria was reduced was predictive of long-term CV protection. Overall, RENAAL indicated that losartan had a beneficial effect on first hospitalization for heart failure—a component of the secondary CV end point of the trial.

In their post-hoc analysis, de Zeeuw et al. identified albuminuria as the strongest independent predictor for both the CV end point and heart failure. Individuals with both high (<u>></u>3.0 g/g) and intermediate albuminuria levels (1.5 to <3.0 g/g) had significantly more CV events than those with low albuminuria (<1.5 g/g). Indeed, an increase of 1 g/g albuminuria was associated with a 17% increased risk for the CV end point and a 26% increased risk for heart failure.

In the study, reductions in albuminuria were highly variable at six months, and as a result, the authors divided the cohort according to their six-month antiproteinuric responses (<0%, <u>></u>0%<30%, <u>></u>30%). CV and heart failure end points occurred more frequently in patients who had little to no suppression of albuminuria. Conversely, the group with the greatest reduction in albuminuria had the greatest reduction in risk for cardiac events, such that for every 50% reduction in albuminuria, the risk of reaching the CV end point was reduced by 18% and the risk of reaching heart failure by 27%.

Importantly, an increased level of baseline albuminuria was associated with an increased risk for a CV event but only in those individuals who also had a renal event, as the authors emphasized. Nevertheless, the researchers concluded that their results are potentially clinically important, as albuminuria is both easily measured as a risk factor for cardiac disease and may thus serve as a marker for the success of cardioprotective strategies.

Summary

Optimal reductions in BP and proteinuria are best achieved through RAS inhibition. Until recently, practitioners used maximally approved antihypertensive doses in high-risk patients but these doses do not necessarily reduce proteinuria. Several studies have tried to show that increasing the dose beyond that for BP control has an effect on proteinuria. SMART has demonstrated that in patients with overt proteinuria, supramaximal doses of candesartan could be safely administered and significantly reduced this end point while maintaining BP control. Consequently, there is now a rationale to go beyond BP control and target albuminuria to reduce renal injury. However, further research is needed to find the dose for optimal proteinuria reduction and its effects on CV outcomes.